Summary / Abstract Obesity represents a major risk factor for the development of hypertension and other cardiovascular disorders, and current therapeutic approaches to prevent and reverse obesity are insufficient. Studies from the NIH and others have demonstrated that human obesity, and resistance to weight loss, is related to the suppression of energy expenditure at rest (termed resting metabolic rate, or RMR). While clinical studies utilizing an array of pharmaceuticals (2,4-dinitrophenol, etc.) have provided proof-of-concept data highlighting the utility of RMR stimulation to reverse obesity, all existing pharmaceuticals that stimulate RMR exhibit unsafe pharmacokinetics and are therefore banned for human use. Development of next-generation therapeutic strategies to combat the obesity epidemic requires increased understanding of the biological controllers of RMR. The hypothalamus, and more specifically the arcuate nucleus (ARC), is critically involved in the integrative control of RMR, and we have recently documented a role for the angiotensin II type 1A (AT1A) receptor, localized to agouti-related peptide (AgRP) neurons of the ARC, in the control of RMR by a diverse array of stimulators including leptin, high fat diet, and the brain renin-angiotensin system (RAS). The objective of the current proposal is to understand the second-messenger signaling cascade within AgRP neurons which is activated by AT1A, and to clarify the neurocircuitry and neurotransmitters which mediate RMR control by the ARC RAS. Based on exciting new unpublished data, we hypothesize that AT1A on AgRP neurons rather uniquely activates a G- alpha-i-2 (GNAI2) cascade, which is sensitive to modulation by regulator of G-protein signaling-2 (RGS2). Further, we hypothesize that this cascade mediates control of AgRP neurotransmission and therefore the activation of melanocortin-mediated signaling through its type-4 receptor (MC4R). Finally, new data support the novel concept that RGS2 also modulates MC4R second-messenger signaling, and is itself regulated by MC4R signaling, which results in an autoregulatory cascade within MC4R neurons that may underlie cardiometabolic sensitization as explored across projects in the current program.